Preparation of 4-alkyl-quinolines



' Patented Oct. 19, 1948 PREPARATION OF 4-ALKYL-QUINOLINES Kenneth Nielsen Campbell, South Bend, Ind., as-

signor to E. I. du Pont de Nemours & Company, Wilmington, Del a corporation of Delaware No Drawing. ApplicationAugust 9, 1944, Serial No. 548,787

7 Claims.

This invention relates to an improvedmethod for preparing 4-alkyl-quinolines, such as lepidine and related compounds which are useful as intermediates in the synthesis of pharmaceuticals.

It is an object of this invention to providean improved process for synthesizin 4-alkyl-quinolines from arylamines and alkyl-vinyl-ketones, whereby to obtain the desired compound in improved yield. Other and further important obiects of this invention will appear as the description proceeds.

The synthesis of a -alkyl-quinoline by theaid of an. alkyl-vinyl-ketone was first described by Blalse and Maire, Bull. Soc. Chim. 4), vol. 3, p. 658 (1908). The authors first reacted aniline with an alkyl-vinyl-ketone to produce a betaanilino-alkyl-ketone; the latter was then heated with aniline-hydrochloride and alcohol to produce the corresponding 4-alkyl-quinoline. The synthesis may be expressed bythe following two equations, wherein Alk stands for an alkyl radical:

It is clear that an oxidizing agent must be employed in the second step of the process. In the reaction of the above authors, presumably contact with the atmosphere was depended upon to supply the requisite oxygen. The above authors have applied the process to the synthesis of 4-ethyl and d-propyl quinolines. They have apparently not applied it to the synthesis of 4-methyl-quinolines.

No yields were mentioned in the above publication, but various other contemporary methods described in the literature, using for instance aniline and a mixture of an aldehyde and a ketone, gave very poor yields. It was not until 1931 that a method was described giving yields of the order of 43 to 58% of theory. and this one was based on the use of aniline and a beta-chloroethyl-ketone (U. S. P. 1,804,045).

I have now 'found that 4-alkyl-quino1ines, cs-

pecially 4-methyl-quino1ine (lepidine), may be synthesized from an arylamine and an alkylvinyl-ketone in a single stepand with exceptionally good yields, if one starts with the hydrochloride of the desired arylamine, and if the reaction mass contains ferric chloride as an oxidizing agent. The reaction is preferably carried out in alcohol as a solvent, which may be alcohol, and may contain further free aniline and a condensing agent, such as zinc chloride. The yields obtained by the improved process are of .the order of 48 to 72% of theory.

Without'limiting my invention, the following examples, in which parts mentioned are by weight, will serve to illustrate my-preferred mode of operation.

Example 1.-Lepidine (4-methyl-quinoline) from methyl-vinyl-ketone 80.9 parts of aniline hydrochloride (0.625 mole), 270 parts of (1.0 mole) of ferric chloride hexahydrate, 10 parts of anhydrous zinc chloride, and 365 parts of 95% ethyl alcohol are charged into a vessel equipped with a reflux condenser. The mixture is heated to an inside temperature of 55-75 0., and 35.0 parts (0.5 mole) of freshly distilled methyl-vinyl-ketone are added slowly over a period of 1 to 1.5 hours. The solution is then refluxed for 1.5 to 2 hours, and allowed to stand overnight. The alcohol is removed by distillation until 320-340 parts are collected, and 150 parts of water are added to the residue. The mixture is stirred and cooled, and made strongly basic by the addition of strong sodium hydroxide solution (25-40%), while the temperature is kept below 25 C. The mixture is concentrated by distillation, and is then heated in an oil bath at 225- 250 C., while superheated steam at 225-250 C. is passed in. The organic layer in the distillate is separated; the aqueous layer is saturated with salt and extracted twice with ether. The extracts and organic layer are combined and dried over magnesium sulfate. The ether is removed by distillation and the residue is fractionally distilled. The yield. of lepidine is 52.? parts, which is equivalent to 73% of the theoretical;

B. P.=90-95/1.52 mm.

Steam at C. can be used in the above procedure for the isolation of the lepidine, but under these conditions a much larger volume ofdistillate is collected. 1

Example 2.--4,6-dimethylquinoline from methyl.- vinyl-ketone The procedure is the same as described under Similar experiments using various other oxidizing agents, such as nitrobenzene, naphthalene, p-nitrophenol and arsenic acid gave very poor yields, which were in fact no better than'using no p e the w ng reag and amounts 5 oxidizing agent at all. Thus, it appears that ferric eing used: 44.? parts (0.313 mole) of p-tol i in chloride is specific in the above reaction, which y de, 135 parts (0.5 mole) of ferric chlofact was not to be predicted on the basis of the ride hexahydrate, 5 parts of anhydrous zinc chlobehavior of other oxidizing agents. ride, 182 parts of 95% ethyl alcohol and 17.5 parts In the above discussion I have mentioned the (0.25 mole) of methyl-vinyl-ketone. The yield 1 optional addition of acondensing agent such as of 4,6-dimethylquinoline is 65% of the theoreti- V zinc chloride. Other equivalent condensing 0 agents are boron trifiuoride or an excess of ferric 20=1.0577. chloride. As will be seen from the above exampies, the condensing agent need be employed in Example g g from 15 catalytic quantities only (less than 0.2 mole per mole of alkylvinyl-ketone), while the oxidizing The Procedure is the same as described above, agent is to be employed in substantially stoichiot e fo low reagents d quantities being used-I metric proportions (2 moles of ferric chloride per 40.4 parts (0.313 mole) of aniline hydrochloride, l of th ket 135 parts (0.5 mole) of ferric chloride hexahy- In heu of t hydrochloride of t 1 m drate, *5 parts of anhydrous zinc chloride, 182 the corresponding hydrobromide may be emparts of 95% ethyl alcohol, d Darts ployed. The arylamine may bear inert substitum of p t -0n h yi ld f ents in the aryl ring, such as alkyl, alkoxy, halomethylquinoline is 24.2 parts or 62% 0f t e t eogen and benzo. In the last-mentioned case a rotioal; 25 4-alkyl-naphthoquinoline results from the proc- 1.6069; d4 =1.0549. ess.

i l Many other variations in the details of pro- ETample 6 ggzgf ggz from methyl, cedure may be made, within the skill of those engaged in the art, without departing from the A mixture of 99.6 parts (0.625 mole) of p-anisi- Spirit of t invention, dine hydrochloride, 270 parts (1.0 mole) of ferric I claim; chloride hexahydrate, 10 parts of anhydrous zinc 1 The process of preparing 4 1 1- ch or d and 365 P s of ethyl alcohol were which comprises reacting a hydrogen halide of a treated at 60 C. (inside temperature) With 35.0 primary arylamine having at least, one free orthop rts mole) of met y y ne- The position with an alkyl-vinyl-ketone in the pres- Droduct was isolated as described above with ence of ferric chloride as an oxidizing agent. superheated steam at 225-250 C. Fractionation 2. The process of preparing a 4-alkyl-quinoline of the ether extracts a d rg n layer of the which comprises reacting a hydrogen halide of a steam distillate yielded a lower-boiling fraction primary arylamine having at least one free ortho- (B. P. 93-95/2 mm), which was shown to be position with an alkyl-vinyl-ketone in an alcop-anisidine, and a higher boiling fraction holic medium and in the presence of ferric chlo- (B. P.=121-123/2 M. P. 28-32 C.) which ride. is G-methoxylepidine. The yield of the latter 3. The process of preparing a i-alkyl-quinoline was 52% of the th oreti al. T fi-m y p which comprises reacting a hydrogen halide of a dine so obtained is the anhydrous form. It can primary arylarnjne having t least one free t be converted to the stable, crystalline hydrate, position ith on alkyl-vjnyl-ketone i 95% 1 M- P- C- y treatment With Water. hol, in the presence of a stoichiometric quantity dilute aqueous alcohol. of errighchloritclile to serve as an oxidizing agent an in 8 ur er presence of a catalytic quan- Emmple Miscellaneous 50 tity of a condensing agent comprising zinc chlo- By following the procedure of the above exid amples, the following additional combinations of 4. The process of preparing lepidine, which r nt d q ntit w re s The yields comprises condensing about 1.25 moles of aniline are given in of the theoretical, based on the hydrochloride with about 1 mole methyl-vinylmethyl-vinyl-ketone used. ketone in alcohol of 95 to 100% strength and in nilino Methl Solvent Aniline 5113173532 12 51531; oxidizing Agent 2 223} gigg g .Moles Moles Moles Percent Abs. alcohol... 1 0.5 0.5 FeC]s.6HzO Nona--. 48 Do 1 0.5 0.5 F6013 anhydrous do 55 95% alcohol... 1 0.5 0.5 FeChfiHzO d 2 Abs. alcohol 0 625 0. 5 d 69 95% alcohol..- 0 625 0.5 do Do 0 .625 0.5 do nOh..- 72

It will be noted from the above table that while the use of a mixture of aniline hydrochloride and aniline gives very good yields, better results are obtained by using the hydrochloride alone in moderate excess (about 25% excess). Also, addition of a condensing agent, such as zinc chloride has a beneficial eifect. The ferric chloride may be in the form of a hydrate or anhydrous. The alcohol may be absolute or 95%, and methyl as well as ethyl.

the presence of about 2 moles of ferric chloride as oxidizing agent.

5. The process of preparing lepidine which comprises condensing about 1.25 moles of aniline hydrochloride with about 1 mole methyl-vinylketone in alcohol of to strength and in the presence of about 2 moles of ferric chloride and less than 0.2 mole of zinc chloride.

6. The process of preparingfi-methoxylepidine which comprises condensing about 1.25 moles of 2,461,610 5 6 p-anisidine hydrochloride with about 1 mole U I TES PATENTS- methyl-vinyl-ketone in alcohol of 95 to 100% 4 N TED STA strength and in the presence of about 2 moles of Number Name Date ferric hloride as oxidizing agent. 7 I 1,304,045 Zollner May 1931 7. The process of preparing fi-methoxylepidine 5 FOREIGN PATENTS which comprises condensing about 1.25 moles of p-anisidine hydrochloride with about 1 mole Numoel 'f Date methyl-vinyl-ketone in alcohol of 95 to 100 548,349 Great Brltam 1942 strehgth an d in the presence of about 2 moles of OTHER REFERENCES 32m chloride and less than 0.2 mole of zmc chlo- -l0 Blaise et a!" BuL Soc Chim de France (4th HIPB Series) vol. 3, pages 658-674 (1908).

KENNETH NIELSEN C Kinner et al., Berichte, vol. 69-3, pages 16-18 REFERENCES CITED (1936)- The following references are of record. in the w file of this patent: 

